Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of metabolic syndrome, characterized by insulin resistance and hyperglycemia, that can lead to ? cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. Recent studies have identified the cJun NH2-terminal kinase (JNK) signal transduction pathway as a mediator of metabolic stress responses. Feeding a high fat diet (HFD) causes increased JNK activity and promotes both obesity and insulin resistance. Studies using tissue-specific knockout mice demonstrate a central role for JNK in the regulation of energy expenditure and the development of obesity. In contrast, JNK in peripheral tissues can cause insulin resistance without changes in obesity. The mechanism that accounts for JNK- dependent insulin resistance caused by feeding a HFD has not been defined. We have identified the PPAR? pathway as a major target of hepatic JNK signaling that contributes to HFD- induced insulin resistance by regulating the expression of the hepatokine fibroblast growth factor 21 (FGF21). We have demonstrated that JNK activation caused by feeding a HFD potently suppresses PPAR? activity. Consequently, disruption of hepatic JNK activity causes increased hepatic PPAR? activity, increased amounts of FGF21 circulating in the blood, and improved glycemia in HFD-fed mice. Disruption of Fgf21 expression prevents the effects of JNK inhibition to cause improved glycemia. Based on these data, we propose that the PPAR?/FGF21 axis mediates the effects of hepatic JNK on insulin sensitivity. The overall goal of this research program is to test the hypothesis that the PPAR?/FGF21 axis contributes to metabolic stress signaling by hepatic JNK. We will examine the mechanism of JNK-mediated repression of PPAR? activity. We will also test the role of the PPAR? target gene Fgf21 as a mediator of JNK-regulated insulin resistance. Achievement of the goals of this proposal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of new mechanisms that contribute to the obesity response. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.